AI
Sunday, October 15, 2017 9:43:58 AM
I have plotted the data from CTAD2106 and PK/PD presentation on this plot. Two lines represent MMSE score for two groups. First, going up is The Strong as defined by slide on CTAD2016 presentation (6 subjects). The other is the group who received lower. medium and also high dose yet did not respond to A2-73. What is common to these subject is that they decline at the same rate though their conditions are different. It is about MMSE delta=-5.5.
The plots show the averages at data points. Statistically significant means that with 95% certainty (or that 95% measurement is certain to follow trend) one can say that from data point to data point the individual measurements changed with the trend. This is roughly 60% for these plots. So they can not be called statistically significant. What it means is that if you have 10 measurements in data point and take another data point measurements if standard deviations defining the dispersion of data points for the set overlap then there is certainty only that say 60% data will follow trend and increase or decrease with it, the rest might not follow the trend. If you look at the individual patients of the 6 Strong this is plainly visible. the averages of measurements meantime create the trend.
The 0 point is the 21 MMSE score which is also the mean for all 32 participants. The set of the Strong started at 22 MMSE so here it is 1. The mean for the rest starts -.25. The plot of the rest is adjusted for the dropouts.
In the first dosing we have the two plots to move in opposite directions. The Strong go down 2 points. The Rest go up 2 points. this is counterintuitive if you look at the later behavior. The first conclusion I can draw is that A2-73 worked on all patients. Yet brain being a complex system, to the change caused by A2-73 reacted in two different ways. Here, I am tempted to say that initial chaos due to changes in physiology of neurons (P300 witnesses it) leads to lasting improvement or to temporary improvement just like DZP, because could it be that magnitude of change is to small to trigger systemic change. I remember when the data for 5 weeks was presented and the change in MMSE score touted to be 1.2 MMSE which is statistically consisted with this plot results, yet the doubters insisted that his was due to DZP dosing at he same time. We do not know whether this was the case. The magnitude of the change is consistent with the improvement due to DZP.
After 5 weeks the plots reverse trends. There is increase and decline about the same rate. by 31 week the increasing Strong flat line, or even slightly decline (41 to 53 weeks), and the Rest do the impossible they reverse and have small rise to 41 weeks then sharply again dive to 53 weeks. The only conclusion can be that some factor has been introduced into the trial which made the the difference. Could it be addition of DZP which would stop The Strong and temporally halt or even reverse the decline of the Rest? Well, as I eagerly awaited the data and poured over it I noticed that every release the data was in general the same yet the labels changed, the format changed so that it was difficult looking at each release to mentally connect in one whole. That is why I replotted the data.
I was excitedly shouted from the roof tops about the “surge” in CTAD 2016 data. Well, the PK/PD data retrieved from slide 26, slope here given in MMSE points per day of trial, does away with it. As if it never existed. The Rest data at 57 basically lies on extended line of 41 to 53 decline. The slope of that line going from base point to purported 57 weeks data was obtained by averaging slopes of individual patients as given on slide 26. The same was done for a grey line going from base point of the Strong to purported 57 week data point for the Strong on slide 26. In the Strong the 57 week point cuts the magnitude of the “surge” by half, yet does not eliminate it. When I looked at CTAD data and took average for all patients as PK/PD suggested at 57 week, the 57 week data point was lying on extension of decline from 41 to 53 weeks, yet plainly in CTAD data this point makes movement of 1 MMSE point up over 4 weeks. Even the 4 week segment seems unusual at this point, not counting the embargo on further
data. Either those making measurements are guilty of gross negligence in collecting and publishing it or Dr M downplays the explosive character of it. Beware of the patent woes!!
From the PK/PD data we have solid 20% of patients stabilized or reversed. The distribution of concentration hints at primery dependence on oral dose so that expectedly those on low contention can be moved up. if the 50% responders in high concentration is a gold standard then we can expect to improve by that amount. If the surge was a genuine phenomenon then it affected all patients regardless previous performance. Yet there is a possibility that at 53 weeks DZP was added and short lived surge was initiated, similar as I claimed to be the case at 31 weeks with the Rest. But then the Strong flatlined which is not even the case at PK/PD data for the Strong this time. But even then it should not prompt anybody to “improve” the data reported at PK/PD per later decline.
Ignore the text with the slope1, it is garbage.
